ASSOCIATION OF AMERICAN MEDICAL COLLEGES COUNCIL OF TEACHING HOSPITALS SPRING MEETING

Washington, D.C.

May 11, 2000

Good afternoon. Serving as Vice President for Health Sciences at the University of New Mexico was an extremely fulfilling experience, and one that provided me with a broad understanding of the challenges and opportunities that one faces in the academic setting. As the old proverb goes, "Only the wearer knows where the shoe pinches." I have worn your shoes--and I have brought that knowledge with me as I returned to the Food and Drug Administration.

As many of you know, we at the Agency have a very broad public health mandate--FDA-regulated products account for nearly twenty five cents of every consumer dollar spent in the United States today. Cutting edge science and technology are providing us with new opportunities and challenges every day. Over the past few decades, we have seen large investments by both the public and private sector in biomedical research and biotechnology.

For example, the total U.S. research and development spending for both NIH and research-based pharmaceutical companies grew from $14.4 billion in 1990 to an estimated $34.9 billion in 1999, an increase of almost 2 1/2 times in 10 years. These investments will result in the development of an abundance of new products that will soon need to be assessed before entry into the marketplace.

In judging these products the Food and Drug Administration touches people's lives in many important ways, every day. For example, FDA products approved in 1999 had a profound impact on many, including: people with rare diseases; people with cancer, arthritis, diabetes, and hepatitis; people living with HIV and AIDS; cardiac patients; and the elderly.

In just the past year, we have seen a new class of drugs for the treatment of osteoporosis in post-menopausal women; new lasers to create tiny holes in heart muscles that could not be treated by an arterial bypass; two new members of a family of drugs for diabetes; two new biological agents for bleeding disorders; and several new combination devices for blood testing and separation.

We also know of many burgeoning new areas of biomedical research that will soon produce other innovative products, including: vaccines for pneumonia-helping to prevent the most common cause of death in the very young and very old; new devices to treat prostate cancer, improve vision and hearing in middle and old age, and identify cancers earlier than ever before. We will be seeing new drugs for Parkinson's disease and Alzheimer's disease, new products to facilitate life saving and life-prolonging cellular and organ transplantation, and new treatments for bioterrorist agents.

As these products enter the marketplace, they will change the very face of health care in America and will help us all lead longer, healthier lives. They will also bring enormous economic benefits, both in lessening the cost of health care and in returning profits on the investments being made in research. These advancements are swiftly moving from the Laboratory into clinical trials and on into the health care market place.

Innovations in science and Technology are the key to miraculous improvements in the quality of our lives and the continued strength of our economy. The fruits of biomedical research promise to improve our health and change the way that health care is delivered. The investments that we are making today will pay out dividends many times over in the future. Having a high performing, science-based regulatory agency like the FDA to render judgments regarding the safety and efficacy of these products reaps public health benefits for both individual citizens as well as the nation as a whole.

While we have the ability to transform our lives and the lives of generations to come by harnessing new biomedical technology, we need to be vigilant about each and every aspect of the products brought to market. Much of the clinical information about the products is being generated in clinical trials conducted at your institutions. Recent incidents at some of them have unfortunately provided a teachable moment for all of us, and unless we learn from these events, we collectively have much to lose.

New scientific advances in the area of gene therapy have tremendous promise, as we have seen from the children in France who appear to have benefited from this technology-yet, grave and disturbing problems in some of the trials conducted in this country have emerged as well. This new area of scientific discovery has been tarnished because many of the most basic rules, which have governed the conduct of clinical investigators for years were not followed.

Here, too, my shoe pinches, for I have worked as a drug monitor and principal investigator, and I have participated on data safety monitoring boards and institutional ethics committees. During my tenure in government, I have spent a great deal of time and effort developing programs that actively recruit subjects for participation in clinical trials. You should know that I feel personally and professionally connected to clinical research, but only to those studies and practices that have met the high standards that patients expect and deserve.

I would not suggest that the entire system is faltering, or that even most investigators are not rigorously conducting clinical trials with the greatest attention to the requisite safety standards for the protection of all subjects. Yet, clearly some researchers at prestigious institutions have failed to follow basic good clinical practices with respect to their conduct of clinical research studies. Any erosion of our system for safe guarding human subjects is troublesome for many reasons-first and foremost, the direct harm caused to the patients. But... the reputations of the investigators, the academic institutions, the research community as a whole, and the whole enterprise of medical innovation are threatened when public trust and confidence is lost.

What we have witnessed-esoteric or complex standards have not been the issue, but rather the most basic elements of what it takes to properly conduct clinical studies.

Enrollment of patients who did not meet the eligibility criteria for the study;

Failure to report adverse events as required.

Failure to ensure that a protocol was followed;

Inadequate training for study staff;

Investigators changing protocols without proper notice to the IRB and to FDA;

Failure to incorporate agreed-upon protocol changes;

Failure to revise informed consent forms as requested by FDA;

Inadequate record keeping and informed consent documentation;

Failure to notify FDA of animal deaths that suggest an increased risk to humans; and

Conflict of interest issues for both investigators and institutions.

I would underscore, these are not isolated incidents occurring on the fringes of science or by physicians with no academic credentials. We have found these problems in some of the most renowned research centers in the country and these unacceptable practices by leaders in their fields of study.

It should go without saying - yet, I feel compelled to - that it is in your interest as leaders and administrators of some of our nation's finest clinical institutions to be sure that faculty who conduct clinical investigations should be well-trained in good clinical practices and conducting trials in a manner that can withstand the highest scrutiny.

I say this to you for several reasons-for patient care; for the reputation of your institution; for the funding of future studies that are reliant upon patient and public confidence; and for the impact on health care in this country.

Why is this happening? Are the cases that have recently emerged just anomalies that should be dealt with but disregarded for the long term? Sadly, I fear not.

I fear that the world of clinical research is evolving in ways that portend continued problems. Let me share with you my views on why we are finding these problems.

First and perhaps foremost, investigators are not adhering to well-established standards for good clinical practices. These are not esoteric requirements or frivolous tasks. The standards for good clinical practices are important at every level, including certain fundamentals-which should be simple tasks-from keeping accurate records and diligently recording data-to the complexity of reporting of adverse events, which often requires skill and a greater degree of judgment in recognition. With respect to the latter, it is critical that any deaths, serious illnesses, or other troubling or unexpected results be reported to all appropriate oversight bodies expeditiously. This information allows those in oversight positions such as FDA to not only make decisions regarding that particular study but similar ones being conducted at other institutions, in order to save additional subjects from illness or injury and allowing us to follow larger trends in related studies.

Second, independent audits have found that IRB oversight of clinical trials has been lacking in overall vigor and quality, and the institutions in which many studies are conducted have not taken responsibility for assuring strong IRB oversight. This is coupled with the disturbing matter of IRB's being kept out of the loop with respect to information that is required to be reported to them by investigators. These practices are taking place in your clinical facilities-you along with other responsible institutional officers need to ensure that your hospital is not the next one with a public health crisis on its hands.

Third, in recent years we also have witnessed a change in the nature of clinical trials-more and more, we are seeing built-in conflicts of interest because academic researchers are serving not only as clinical or principal investigators, but also in other roles such as sponsors of the IND investigations, patent holders, and product manufacturers. Financial incentives are an important part of what has driven technological advancements in this area. As a result of these new arrangements, it has never been more important that you ensure that adequate controls are in place to guard against improper behavior caused by conflicted loyalties on the part of researchers. The institutions or individuals at your institutions serving as sponsors are expected to meet and will be held to the same standard as any pharmaceutical company.

Fourth, researchers must also continue to ensure that clinical trial subjects have a very clear understanding of the risks involved in participation in the trials, as well as an understanding of what, if any, benefit will be enjoyed by the subject for his or her participation. Use of subjects without legally effective informed consent under the guise of the furtherance of science conjures up images of past injustices. We must be extremely careful to ensure that subjects are not exploited by those driven to find the next blockbuster miracle drug.

Finally, we in government also bear a responsibility. We, too, have been criticized-for the inadequate amount of resources that have been devoted to this issue; the limited range of enforcement options that can be implemented swiftly and effectively; as well as allegations of insufficient coordination and overlapping jurisdictions among Federal agencies, particularly FDA and NIH. The Department of Health and Human Services is developing a plan of action that will soon be announced by the Department which will include both administrative and statutory changes that will be implemented or requested to address some of these critical issues.

Even as I acknowledge that there are shortcomings on the part of the Federal government, I hasten to note that this system is less dependent on new policy making and policing than on making sure those involved know and understand and follow the current rules of the game.

This is not a situation where we have suddenly changed the requirements that these investigators must follow. In fact, it is just the opposite-we have clearly outlined our expectations for Good Clinical Practices. These practices are used as international standards for how to appropriately conduct clinical trials, and are used in courses around the country to teach investigators about the rules that they need to follow.

This system involves shared responsibility-shared between the industry, institutions and IRBs, clinical investigators, and government regulators. We at FDA have implemented Good Clinical Practices in the United States through regulations and guidance, and have enforced these practices both in our review process as well as our on-site inspection program. If clinical investigators at your institutions are not extremely familiar with and following these Good Clinical Practices, they certainly need to be.

Some have suggested that some of the recent events in the gene therapy clinical trials were the result of bad luck, not avoidable mistake. But, the famous Brooklyn Dodgers manager Branch Rickey once commented that "Luck is the residue of design." We have the power to control these studies, develop protocols, and follow them closely. Through design, we can ensure that patients are adequately protected when they choose to enroll in a clinical trial. By maintaining high standards and requiring that all investigators adhere to them, we can stand behind the trials that we are recruiting subjects for.

Thank you very much for inviting me to be here today to speak to you on this issue, I look forward to our work together in the future.